Roadblocks confronting widespread dissemination and deployment of Organs on Chips

Organ on Chip platforms hold significant promise as alternatives to animal models or traditional cell cultures, both of which poorly recapitulate human pathophysiology and human level responses. Within the last 15 years, we have witnessed seminal scientific developments from academic laboratories, a flurry of startups and investments, and a genuine interest from pharmaceutical industry as well as regulatory authorities to translate these platforms. This Perspective identifies several fundamental design and process features that may act as roadblocks that prevent widespread dissemination and deployment of these systems, and provides a roadmap to help position this technology in mainstream drug discovery.

Organ on Chip platforms hold significant promise as alternatives to animal models or traditional cell cultures, both of which poorly recapitulate human pathophysiology and human level responses.Within the last 15 years, we have witnessed seminal scientific developments from academic laboratories, a flurry of startups and investments, and a genuine interest from pharmaceutical industry as well as regulatory authorities to translate these platforms.This Perspective identifies several fundamental design and process features that may act as roadblocks that prevent widespread dissemination and deployment of these systems, and provides a roadmap to help position this technology in mainstream drug discovery.
While traditional 2D culture methods have served the scientific community well over the past century, the development of Organ on Chip devices has improved the ability to culture more complex 3D engineered and ex-vivo tissues [1][2][3][4][5][6] .Conceptually, Organ on Chip devices are continuously perfused microfluidic devices used to culture cells or engineered tissues in a way that models tissue-and organ-level functions within a minimal functional unit.These microfluidic devices can range from simple systems with one or more related cell types [7][8][9][10] to more complex multichannel systems that utilize porous membranes and multiple cell cultures to mimic tissue interfaces, such as those in the lungs or kidney [11][12][13][14][15] .Multiple Organ on Chip devices have been linked together to analyze the interactions between different organ functions in the context of drug or toxin delivery as well as metabolism and other multiorgan processes 5,[16][17][18][19][20][21] .For example, vasculature or immune cells can be co-cultured with various types of organoids 22 .More complex models can be created by fusing different types of organoids generated separately to reconstitute the interaction of multiple tissues 23,24 .A notable example of a complex Organ on Chip is the EVATAR system for female reproductive systems 14,[25][26][27] , which includes separate organ modules for the ovary, fallopian tube, uterus, cervix, and liver within a microfluidic system to simulate the in vivo female reproductive tract.The development of new Organ on Chip devices centers around the incorporation of physiologically relevant mechanical and fluidic parameters, such as shear stress, mechanical strain and compression, and perfusate composition, which includes but is not limited to additional suspended cells (e.g.immune cells), stimulants (e.g.hormones and drugs), and gaseous species (e.g.oxygen and carbon dioxide) 1,5,28 .The inclusion of flow has been shown to help mature cell cultures by mimicking the phenotypical characteristics of the comparable in-vivo system 1,29 .Additionally, Organ on Chip devices are designed to utilize an ever-growing array of analytic techniques to assess the functionality and biomechanics of the tissues cultured within them, such as live-cell imaging, analyte collection, and electrophysiological readouts 2,3,16,[29][30][31][32] .The continued advancement of microfabrication and tissue engineering technologies has helped to make Organ on Chip devices an optimizable cell culture platform capable of recapitulating the in-vivo micro-physiological environment of a variety of organ systems.
With more robust recapitulation of physiological microenvironments compared to traditional 2D cultures, Organ on Chip devices have begun playing a more significant role in translational science work, especially within the field of drug development.The minimal functional unit of an organ that exists within an Organ on Chip provides an accurate physiological microenvironment that is essential for drug development and risk profiling 29,33 .Recapitulation of a specific disease microenvironment ensures that the efficacy of a drug-both in terms of its function and its targeting to a specific organ system-can be appropriately validated in the early stages of drug development [34][35][36] .
When compared to animal models commonly used at this early stage of drug development, Organ on Chip models can be more effective at identifying potentially useful novel therapeutics because these models use tissues and cell lines derived from human samples 33,37 .A humanbased drug discovery model ensures that when potential new drugs are identified, the drug actually targets the human receptor or pathology.Without this validation of human specificity, prior drug discovery trials have fallen flat once they move past animal testing into pre-clinical testing 38 .Additionally, these human Organ on Chip models provide a significantly more accurate analysis of drug toxicities for potential new drugs compared to animal models in the pre-clinical phase, since they are also able to demonstrate side effects in human tissue that might not be present in animal models 36,[38][39][40] .Aside from the biological benefits to drug discovery, Organ on Chip devices can also be run at a high throughput, meaning that many potential new drugs can be tested in rapid succession or even concurrently [41][42][43] .Because of these physiological and experimental advantages of Organ on Chip devices over traditional animal models, Organ on Chip devices offer a promising new pathway within the pharmaceutical industry.

Outline
Traditional animal models and cell cultures both poorly recapitulate human pathophysiology and human level responses.Organ on Chip platforms, on the other hand, allow researchers to exert control over tissue composition and architecture by providing an array of cellular and extracellular cues to then precisely recapitulate the minimal functional unit of human tissues or organs.This decade has witnessed seminal scientific developments from academic laboratories, a flurry of startups that seek to translate those platforms, and a genuine interest from pharmaceutical industry as well as regulatory authorities.The individual and collaborative efforts of these important stakeholders will undoubtedly continue to refine and mature Organ on Chip platforms.It is imperative, therefore, to identify any fundamental design and process features that might ultimately prevent widespread dissemination and deployment of these systems.In this perspective, we examine several such barriers.First, we discuss the various stakeholders in the development of Organs on Chips, and their roles and responsibilities throughout the process.Second, we highlight the complications associated with polydimethylsiloxane (PDMS), the widely used material for Organ on Chip fabrication and discuss alternatives.Third, we discuss the engineering design process that will facilitate fully functional Organ on Chip platforms.Finally, we examine the pathway to adoption by the pharmaceutical industry, especially given the FDA Modernization Act 2.0.We submit that recognition and rectification of these barriers is especially timely, as these technologies are beginning to be tested and validated by the intended end-users: disease biologists, pharmaceutical companies, and regulatory authorities.

The translational landscape of Organ on Chip technology
Following the landmark publication of Lung on a Chip in 2010, and robust support from funding agencies, Organ on Chip technology has become one of the fastest growing areas in bioengineering 12 .While the foundational use of Organs on Chips can be attributed to the academic convergence of microfluidics, stem cell technology and tissue engineering 44,45 , one of the major current driving forces is the interest of pharmaceutical companies in applying this technology to drug development.As a result, an ecosystem of new biotechnology companies has emerged to help move Organs on Chips out of academic research labs and into the drug discovery space 33,46 .In the US, startup companies have been spun out of academic institutions primarily focused on providing research services that utilize unique Organ on Chip models 47 .In Europe, the expansion of Organ on Chip technology is being driven by 3D organoid companies and microfluidic companies looking to add Organ on Chip applications to their portfolios 48 .The value proposition for many of these startups focuses on providing better data for lead optimization 49 .However, Organ on Chip platforms face many technical and regulatory barriers that may complicate their widespread adoption in industrial use, and in pre-clinical trials 50 .
The landscape for new drug development is one of the most daunting of any product development pipeline.The estimated average cost for pharmaceutical companies to bring a new drug to market is approximately 2 billion dollars, and the process can take upwards of 15 years 33,51 .Despite this huge investment of time and money, the clinical success rate of drug approval stands between 10 and 20% 52,53 .This problem, however, is not new.The high attrition rate and overall decline in pharmaceutical research and development efficiency has been well documented for over 30 years 54,55 .A recurring culprit has been animal models, which are not sufficiently predictive of the safety nor efficacy of therapeutic compounds in humans 29,56,57 .The United States Food and Drug Administration (FDA) traditionally required data from animal studies, such as safe starting doses and potential toxicity levels, to ensure that human clinical trials can be safely conducted.While traditional high-throughput drug screening methods are effective at eliminating ineffective drugs, the process is often not conducive for these early stage systemic toxicity studies 58 .As an alternative model to animal studies, Organs on Chips provide this safety information as well as genetic toxicity, pharmacokinetics, ADME (absorption, distribution, metabolism, and excretion), reproductive toxicity, and carcinogenicity 34,59 .Aside from the direct effects of a potential drug on the tissue of interest, as would be screened for in highthroughput drug screenings, Organs on Chips have the ability to address systemic toxicity concerns via the linkage of several different types of Organ Chips 60 .Through the linkage of different chips, the effect of drugs on liver function or kidney function can be tested in conjunction with the effect of the drug on a primary tissue 3,4,61 .The use of multiple chips in series and parallel with each other can mimic the natural progression of a drug through different body compartments and provide more information on the potential systemic toxicity of a drug, aiding in the exclusion of toxic drugs at an earlier stage in the drug identification process 5,62 .
The US Food and Drug Administration (FDA) and other regulatory agencies are conceptually supportive of new approaches and have communicated strategies that are being considered to put this acceptance into practice.To this end, the FDA formed an Alternative Methods Working Group focused on standardization of both new and existing in vitro models to ensure that the data that are generated are comparable and of the highest quality, and that studies are robust, reproducible, relevant, and fit for purpose.The Alternative Methods Group also facilitates interactions with global regulatory bodies interested in implementing alternative methods in toxicology.In response to the 21st Century Cures Act of 2016, FDA also launched its Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program, which is designed to support the development and, in some cases, qualification of novel approaches to drug development for use in regulatory decision making.Further, with the passage of the FDA Modernization Act 2.0 in 2023, animal testing requirements have changed and opened a pathway forward for widespread use of Organs on Chips.The excitement around the prospect of Organ on Chip technology to make a significant and sustained impact on drug discovery pipeline could not be higher.Applying the Gartner hype cycle paradigm for emerging technologies to Organs on Chips (Fig. 1), if the initial landmark publication and bold funding investments were the initial 'innovation trigger', we might be at the 'peak of inflated expectations' now.We submit that if technology providers, intended technology consumers, and regulatory agencies engage early and often, Organs on Chips can perhaps bypass the 'trough of disillusionment' that's often triggered by implementation failures.Concerted efforts of all stakeholders can help define broad market applicability and relevance of these novel technologies, eventually leading to mainstream adoption.

Organ on Chip stakeholders
Here we will discuss the roles and responsibilities of stakeholders within Organ on Chip development: engineering developers, biologist adopters, Organ on Chip startups, pharmaceutical industry, and regulatory bodies (illustrated in Fig. 2).It is important to note that while the roles and responsibilities of each of these parties differ, they are not wholly disjointed.It is also not an exhaustive list of all stakeholders.However, the design and dissemination of a validated Organ on Chip that is readily available, usable, and of value to end-users requires collaboration and partnership between all these stakeholders.
Engineers are responsible for bringing the engineering skills and knowledge necessary to construct a functional Organ on Chip and its associated control systems in an iterative design, build, test process.It is imperative for engineers to properly understand the in-vivo biomechanical and environmental niche for translation into a minimal functional unit that can represent tissue-and organ-level functions.Other biomechanical and environmental factors to consider may include culture temperature, flow directionality, basement membrane characteristics, biochemical gradients, oxygenation, and mechanical perturbations, etc.Not only should the biomedical engineer consider the physical and biological needs of a modeled system, but also the experimental desires of the end-user, whomever that may be.Chips should be designed to interface with established experimental tools and methods of analyses such as live-cell imaging, analyte collection, electrophysiological readouts, and any other offline tools.The materials used and mode of fluidic control should also be made with the end-users manufacturing capabilities, skillset, and desired scalability in mind.
Biologists are in part responsible for appropriately identifying the minimal functional unit necessary to address a specific biological question, its biological components, and investigative needs.In the instance of non-existent or poorly functioning cell lines, they help in the development of the cell lines, tissues, organoids and assembloids to be studied within Organs on Chips.As the stakeholder that brings the most biological knowledge to Organ on Chip development, the biologist is also responsible for helping to validate the biological and functional readouts from the device.As a cyclic development process, their role is neither truly at the end or beginning of the development and is essential at all stages.
The role of Organ on Chip startups and related industry is to establish the translational relevance of their technologies.They must understand the performance metrics, ideal context of use, and performance limitations of their platforms so that they can be benchmarked favorably against current standards, and so that they may appropriately interpret the results from pre-clinical trials.This is also central to being able to effectively manage investor and public expectations of device capabilities.Regulatory bodies assess the readiness of these approaches for specific context of uses, and ultimately make the decision to qualify them as a drug discovery tool.
As one of the primary end-users, the pharmaceutical industry evaluates the value proposition of a specific Organ on Chip technology based on whether it can be used for internal decision making, or if indeed, the technology has been qualified as a drug discovery tool.Important considerations such as throughput of readout, reproducibility of data, and compatibility with automation often drive decision making.Other potential end-users include disease biology laboratories that often do not have traditional engineering skills or microfluidics experience.Thus, user needs can vary greatly; hence the design and dissemination strategy of Organs on Chips requires careful consideration of the context within which platform will be ultimately used.

Materials and manufacturing of Organs on Chips
Traditional polydimethylsiloxane (PDMS)-based microfluidic devices utilize a combination of photolithography and soft lithography to generate enclosed microscale channels for fluidics and cell culture (Fig. 3A).Just over a decade after its discovery, this method was adapted to layer intricate microfluidic channel geometries and porous structures to develop the first Organ on Chip, and the majority of subsequent Organ on Chip designs 5,12,63 .PDMS has become the material of choice for Organs on Chips due to properties that make it suitable for biological applications, such as low cytotoxicity, optical transparency, gas permeability, and established fabrication methods 64,65 .Despite the adoption of PDMS as the standard material for prototyping Organs on Chips, many limitations have been identified 5,66 .Adsorption of hydrophobic compounds and leaching of un-crosslinked oligomers have provided the greatest hindrance to the adoption of PDMS-based Organs on Chips for drug discovery assays.Significant work has been done to model the adsorptive properties of PDMS to optimize design parameters that minimize adsorption and mitigate the impact of PDMS on drug discovery studies 67,68 .Aside from optimizing Organ on Chip geometries, PDMS adsorption has been combated by the use of coatings such as parylene c and polyphenol that decrease gas and solvent permeability in PDMS 68,69 .Additionally, due to the limitations of the photolithographic fabrication method, the channels in PDMS-based microfluidic devices have a maximum height of approximately 200μm 70 , which typically prohibits their use for culture of large spheroids and organoids.Given the inherent limitations of PDMS, there is a need to develop Organs on Chips from alternative materials.
Within the Organ on Chip community, the problems with PDMS are well known.There is extensive literature on the fabrication and use of plastic based microfluidic devices, which may serve as an alternative to PDMS based Organs on Chips [71][72][73][74] .Plastics such as polymethyl methacrylate (PMMA or acrylic) became a popular alternative to PDMS because of their manufacturing ease and similar biological and experimental benefits, such as optical clarity and being bioinert 3,4,61,72,75 .Plastic-based Organs on Chips can be fabricated by methods such as micromilling, 3D printing, and injection molding, that each offer a benefit at different stages of development and use 74,76 .
Thermoplastic-based Organs on Chips can readily be fabricated via micromilling (Fig. 3B), a subtractive manufacturing technique where selective removal of a base substrate generates microscale features in the substrate 3,4,61,77 .Organs on Chips with a similar level of complexity to traditional PDMS-based Organs on Chips can be fabricated by micromilling machines using computer numerical control.Computer aided design models are implemented using software such as AutoCAD or SolidWorks.Once translated into milling code, a multiaxis mill removes material from the workpiece to form the final chip design.The size limitations of micromilled features depend on the minimum step size of the axis motors and the total number of axes; more advanced milling machines often have smaller motor steps and more moveable axes that allow for fabrication of smaller and more complex features 3,61,78,79 .Micromachined platforms are also more accessible for in-house prototyping as micromilling machine can easily be setup in most lab spaces without a cleanroom 78,79 .In-house prototyping also allows for rapid iteration between new designs.
As with micromilling, 3D printing can be utilized to fabricate complex Organs on Chips.3D printing is a form of additive manufacturing that relies on the sequential deposition of substrate layers to form a final product (Fig. 3C).While there are several types of 3D printers, including polyjet printing, selective laser sintering, and stereolithography, they all rely on the localized deposition or solidification of material in a single XY plane.Once the individual layer is complete, the extrusion head or platform moves in the Z axis to start fabrication on a new layer.The overall complexity is limited by the minimal layer height and XY resolution of the printer used.By sequential layering material, 3D printing allows for the fabrication of complex overhangs and structures that are impossible to form by micromilling or injection molding.As with micromilling, 3D printers can be a valuable tool for in-house rapid prototyping due in part to the low cost and small lab footprint required to set up a 3D printer.With the use of larger and more complex 3D printers, the fabrication of Organs on Chips by 3D printing can be scaled to industrial use.As such, 3D printing is useful for the development phase of Organs on Chips as well as the production for widescale use.
Once an Organ on Chip design is finalized, a popular method for its mass production is injection molding (Fig. 3D).This process is very cost-efficient at large scales and can rapidly produce identical plasticbased devices.The process requires that a negative mold be machined, in two or more parts that can be clamped together to form a mold with a cavity that mimics the designed final product.Thermoplastics are then heated up and injected into the mold completely filling the cavity.The plastic is then allowed to cool and set within the mold before being taken out.This process can be easily scaled by serially filling sets of linked base molds at a time and removing the excess material between plastic devices post-fabrication.Because the molds can be reused numerous times, the process has a high start-up cost, but is incredibly cost-efficient when used at a large scale.The cost-efficiency of injection molding makes it a prime fabrication technique for industrial use of Organs on Chips while its high start-up costs may limit its use for initial prototyping.
Plastic microfluidic devices, fabricated through micromilling, 3D printing, and injection molding are a viable alternative to PDMS for Organs on Chips.Each of these methods comes with benefits and drawbacks that may alter which method is used depending on the development stage of an Organ on Chip or the end-user.Regardless of the manufacturing method, plastic-based Organs on Chips are becoming more popular at all stages of Organ on Chip development.It is especially important that they be considered early in the prototyping stage to avoid the need to revalidate Organ on Chip devices as they move between stakeholders and require iterative redesigning.However, widespread dissemination and use of Organs on Chips also requires the development of a complete microfluidic system, including peripheral support and analytic devices that allow Organs on Chips to be usable to perform a wide array of biologic experiments.

Platform development for Organ on Chip operation
From a broader perspective, a complete Organ on Chip system requires additional components, such as electronics, software and fluid handling systems.Therefore, a systems engineering approach is necessary to design and manage the various components required for a practical platform [80][81][82] .This often requires a multidisciplinary engineering approach that combines mechanical, electrical, and computer engineering, with the added unique considerations of developing living biologic systems 83 .Based on the end-user needs and workflow, basic functional elements are conceptualized and arranged to develop the platform configuration.Next, functional elements are identified and grouped to determine the most vital components of the platform.Organization elements at this stage can help identify key features of the design and decrease time required to address potential failure modes 84 .This process can also be used to effectively bring stakeholders together and facilitate conversation around needs and expectations.Overall, careful planning and understanding of the processes involved in operation of an Organs on Chips is vital for the development of useful devices and systems.In the coming adolescence of Organs on Chips, we are starting to see the development of more complete platforms, which are only just becoming commercially available.

Pathway to adoption
Translational relevance is the anchor for any new non-clinical model system (cell based assay, Organ on Chip platform, or animal model) that is intended to help understand, prevent, or treat a human condition.The principles that define translational relevance include: replication of human physiology and pathophysiology (organ responses or disease state/pathogenesis), genetics, epigenetics and/or the molecular biology of human cells.New approach methodologies such as Organs on Chips will be expected to meet translational expectations if they are to be broadly adopted to decrease reliance on animal models in drug discovery and biomedical research.Gaining sufficient legitimacy based on the performance (track record) of the approach is key to the successful adoption by scientists and organizations.Once a method demonstrates that it is equivalent or superior to other models for predicting or explaining human conditions or outcomes, it may be  adopted as a model of choice.Ultimately, an Organ on Chip's performance determines whether the technology or approach can be used to answer a defined and specific research question.Although all new approaches start with performance uncertainty, resource investments that serve to reduce the uncertainty are required to accelerate adoption.Important components of a pathway to adoption, and their inclusion in a drug discovery pipeline include Validation, defining Context of Use, Qualification as a drug discovery tool that is Fit for Purpose, and finally, Benchmarking 85,86 .
Validation process starts with assessments of platform sensitivity, specificity, precision, robustness, reproducibility, and stability.It also seeks to define the similarity between the endpoint generated by the Organ on Chip and the clinical readouts, as well as the predictive demonstration of clinically effective interventions producing a similar  effect in an Organ on Chip platform 87 .Defining Context of Use involves identifying the exact utility of the emerging technology.It describes the conditions under which the Organ on Chip is to be used successfully in performance of a task, and what one should expect it to do.Qualification is the process of determining whether the Organ on Chip is suitable for its intended purpose based on pre-determined performance criteria.Qualification process is also intended to explain how results of the approach will be used in decision-making 88 .A Fit for Purpose statement indicates that the Organ on Chip assay or approach has "good enough" validation/qualification information to support its context of use 89,90 .Ultimately, the end-user will often conduct Benchmarking studies to rigorously compare the performance of different methods using well-characterized internal benchmark datasets, to provide guidance for improvements in the current platform, or guide investment in alternative platforms.
Qualification scheme for any emerging technology or method is highly dependent upon the complexity of the questions (or mechanistic hypotheses) and the pathophysiology necessary to answer these questions 91,92 .For example, if an Organ on Chip technology is expected to reduce reliance on an animal model of pulmonary fibrosis, then the new approach would be expected to recapitulate the underlying molecular and cellular mechanisms that are present and relevant in humans.Expectations for stringency of the qualification process relate to how the data will be used, the decisions they will inform, and the potential consequences of those decisions for human health.For example, the expectations for stringency may differ when the context of use is the safety evaluation of a novel drug versus a basic biology application such as understanding host-pathogen interactions 93 .

Summary
The rapid development of Organs on Chips, primarily driven by interest from pharmaceutical companies, has led to a need for industry standards for the field.However, standardization cannot stifle innovation.Properly addressing the translational barriers for various applications is key for Organs on Chips to reach their ultimate potential.While the resolution of these barriers should diminish the trepidation of slow adopters, dialog with industry partners will help in defining important milestones, such as throughput, cost per data point, and demonstration of value proposition in terms of cost and time savings.By facilitating an understanding of individual stakeholder roles in the development of Organs on Chips, they can be more easily implemented at multiple stages of drug discovery and development.However, deliberate care should be taken to avoid narrowing the scope of Organ on Chip technology solely to drug discovery and highthroughput applications desired by pharmaceutical companies.Instead, all the potential end-users should be kept in mind throughout the development and dissemination phases of Organ on Chip technologies.The widespread dissemination of Organs on Chips requires a recognition that this highly interdisciplinary effort is not only scientifically fertile, but also requires ushering in a new framework for scientific endeavors where engineers, scientists, industry, funding agencies, investors, and regulatory bodies are all contributing at each phase of development for these highly innovative and impactful systems.

Outlook
Once the framework for the widespread dissemination and deployment of Organs on Chips herein proposed is accepted and used by the general scientific community, Organs on Chips have the potential to become a core research tool for basic biological sciences, translational clinical sciences, and also to aid the passage of novel therapeutics from bench to bedside.For basic biological science research, Organs on Chips can provide models of many organ systems-either through the culture of ex-vivo tissue samples or tissue engineered samples-that match the cellular, physiologic, and genetic profile of a human more accurately than 2D culture models or animal models.Translational sciences like the pharmaceutical industry will greatly benefit from the high throughput testing of potential therapeutics within Organs on Chips without risking the human insensitivities that have plagued traditional animal models in the pre-clinical testing phase, such as the loss of targeting when moving from mouse to human models or the presence of toxicities in humans that are not present in other species.Looking beyond the uses of Organs on Chips in the realms of research and development, their widespread usage in basic sciences and industry as well as their continued adoption by regulatory bodies will help open up the potential clinical uses of Organs on Chips for personalized medicine.Through the use of cell lines derived from an individual patient, Organs on Chips could be used to identify therapeutics that have the most specific impact for the patient while also minimizing their individual risk for adverse side effects.Organs on Chips have the potential to be widely used in a clinical setting to identify the best option from a variety of drug options just as bacterial cultures are used to select for specific antibiotics.In order to unlock these practical and promising clinical uses of Organs on Chips, we must begin by encouraging the widespread dissemination and deployment of Organs on Chips within the scientific community and relevant regulatory bodies.Without further dissemination, Organs on Chips are at risk of becoming a niche experimental tool.While trying to position an Organ on Chip platform within mainstream drug discovery, it is reasonable to adopt principles of translational relevance to define qualification and/or validation pathways and to establish a well-defined context of use.Following the framework we have herein described, the scientific community and regulatory bodies can collaborate to form best practices for the use of Organs on Chips and facilitate their adoption within new areas of research.As Organs on Chips become more widely used and accessible, the full potential of these devices may be realized.

Fig. 1 |
Fig. 1 | Gartner hype cycle for Organs on Chips.The Gartner hype cycle for Organs on Chips demonstrates how key events in the development of Organs on Chips can stimulate expectations of Organs on Chips within the scientific and general community.It also warns of the potential disillusionment that can occur if Organ on Chip dissemination is limited by a lack of stakeholder engagement.

Fig. 2 |
Fig. 2 | Stakeholder engagement in the iterative development process of Organs on Chips.A visual representation of the cyclic and iterative process that is critical to the development and usage of Organs on Chips.Within each segment, the general roles of individual stakeholders are highlighted in their individual iterative process as well as their role moving towards widespread dissemination of Organs on Chips.

Fig. 3 |
Fig. 3 | PDMS and plastic based manufacturing methods for Organs on Chips.A Photolithography based Organ on Chip fabrication begins with the formation of a mold with raised features via standard photolithography methods.PDMS can then be cast onto the mold to form a PDMS chip with negative spaces that form the microfluidic channels of the final PDMS-based Organ on Chip.B Micromilled Organs on Chip devices are milled via subtractive manufacturing techniques.Micromachining tools remove excess material from a plastic substrate resulting in the formation of the channels and features of an individual Organ on Chip.C 3D printed Organs on Chips are formed by the sequential deposition of a thermoplastic in thin layers to form the shape and features of an Organ on Chip.D Injection molded Organs on Chips start by the creation of a reusable external mold with positive features that correspond to negative spaces in the Organ on Chip design.The mold can then be filled with a liquid thermoplastic.Once the thermoplastic has set, the molded Organ on Chip can be removed from the mold.